International Patent PCT/AU89/00350 (WO 90/01938) incorporated herein by reference, discloses certain phosphosugars and phosphosugar containing compounds as potent anti-inflammatory agents, and the use of these compounds as anti-inflammatory agents in animals and man. In particular, mannose-6-phosphate was shown to have anti-inflammatory activity against cell-mediated inflammatory diseases such as experimental autoimmune encephalomyelitis, adjuvant-induced artries and delayed type hypersensitivity in experimental animals.
In the work leading to the present invention, the inventors have found novel derivatives of mannose-6-phosphate and other phosphosugars which have more potent anti-inflammatory activity than phosphosugar compounds previously identified, and many of these novel compounds have pharmacological and physicochemical properties that are superior to those of the simple phosphosugars. These agents function by binding to certain receptor molecules (for example the mannose-6-phosphate receptor(s) or tile insulin-like growth factor II receptor), on the surface and/or inside cells, for which mannose-6-phosphate is an integral part of a natural ligand. These agents, when present, can effectively inhibit the ability of inflammatory leukocytic cells to cause inflammation and can inhibit the pathological sequence associated with inflammation.
The mannose-6-phosphate receptor is a multifunctional receptor and, in addition to binding degradative enzymes to the cell surface (1), it can also bind certain cytokines and growth factors, such as transforming growth factor-beta (TGF-beta) (2) and insulin-like growth factor II (1,3), which may have roles in inflammation and its sequels TOF-beta is one of a superfamily of signaling molecules which play important roles in modulating cell growth (4). TGF-beta, is a potent fibrogenic cytokine, and thus is probably important in scar tissue formation (5) as an integral part of the inflammatory response. Thus, another part of the anti-inflammatory effect of mannose-6-phosphate-containing compounds is their potential to block the effects of cytokine and/or growth factors in inflammation by blocking their binding to the mannose-6-phosphate receptor. While it is not intended that the present invention should be restricted in any way by a theoretical explanation of the mode of action of the novel phosphosugars in accordance with the invention, it is presently believed that these active compounds may exert their anti-inflammatory effect by acting as antagonists or competitive inhibitors of the natural ligands of mannose phosphate receptors on and/or in cells.
Accordingly, the active novel phosphosugars and novel phosphosugar containing compounds include compounds which are effective as competitive inhibitors or antagonists of the cellular receptors for which mannose-6-phosphate is wholly or an integral part of the natural ligand.